Letter Cite This: Org. Lett. 2018, 20, 5444−5447
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Diastereoselective Total Synthesis of Raputindole A Mario Kock and Thomas Lindel* TU Braunschweig, Institute of Organic Chemistry, Hagenring 30, 38106 Braunschweig, Germany
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S Supporting Information *
ABSTRACT: The first diastereoselective total synthesis of the bisindole alkaloid raputindole A is reported. After Au(I)-catalyzed assembly of the cyclopenta[f ]indole tricycle, it was possible to hydrogenate the indene double bond regio- and diastereoselectively through iridium catalysis, guided by a preinstalled hydroxy function. Attempted HWE reaction led to formal elimination of formaldehyde from an α-quaternary cyclopentane carbaldehyde, which was circumvented by Takai olefination. After Suzuki−Miyaura cross coupling and deprotection/oxidation, (±)-raputindole A was obtained in 13 linear steps in 18% overall yield.
T
OH groups mainly concerns the mono reduction of 1,4dienes,9 in addition to 1,2-10 and remote alkenes.11 The literature regarding 1,3-dienes is surprisingly scarce.12 Even simple 1-hydroxymethyl-1H-indene derivatives have not been subjected to diastereoselective homogeneous hydrogenation. The synthesis of raputindole A (1) starts from N-TIPS-6iodoindoline (2, Scheme 1),13 which underwent quantitative Sonogashira coupling with ynol 3, synthesized by O-TIPSprotection of hydroxyacetone and a Grignard reaction with ethynyl magnesium bromide.14 The obtained 6-alkynylindoline
he unique terpenoid bisindole alkaloid raputindole A (1, Figure 1) was isolated from the rutaceous tree Raputia
Figure 1. Bisindole alkaloid raputindole A (1) from the Amazonian tree Raputia simulans Kallunki.
Scheme 1. Synthesis of the Tricyclic Core of Raputindole A (1) and Introduction of the Isobutenyl Side Chain
simulans Kallunki in 2010.1 The rare cyclopenta[f ]indole core of 1 can also be found in nodulisporic acids,2 shearinines,3 and janthitrems,4 which exhibit a fully substituted indole enamine section. An unsubstituted enamine section can be found in the trikentrines5 and herbindoles.6 Cyclopenta[f ]indole systems have been accessed synthetically from indene-based starting materials involving late-stage indole synthesis.7 Recently, we reported the first total synthesis of raputindole A (1) that featured a regioselective Au(I)-catalyzed cyclization of a 6-alkynylindole precursor to the cyclopenta[f ]indole system of 1. The resulting indanone moiety had to be functionalized further by conversion to the alkenyltriflate, followed by installation of the isobutenyl side chain by Pdcatalyzed cross coupling with potassium isobutenyl tetrafluoroborate. A critical step remained the reduction of the resulting indene to the indane moiety in the presence of a conjugated isobutenyl side chain and an isolated monosubstituted double bond.8 While the regioselectivity of that step was convincing and complementary to that of catalytic heterogeneous hydrogenation, the diastereoselectivity was low, requiring separation by chromatography. Thus, we decided to investigate a diastereoselective total synthesis of raputindole A (1). We envisaged a tethered homogeneous hydrogenation that would guide both hydrogen atoms onto the indene double bond syn to a preinstalled hydroxymethyl moiety. Regio and diastereoselective hydrogenation of dienes exploiting directing © 2018 American Chemical Society
Received: July 25, 2018 Published: August 28, 2018 5444
DOI: 10.1021/acs.orglett.8b02349 Org. Lett. 2018, 20, 5444−5447
Letter
Organic Letters was acetylated to give cyclization precursor 4. Employing the “preactivated” Au(I)-catalyst Au(PPh3)NTf2,15 followed by methanolysis afforded the desired cyclopenta[f ]indoline 5 in pleasing quantitative yield. A sequence of α-deprotonation, triflation of the enolate (PhNTf2, LHMDS), N-TIPS deprotection (2 N HCl), Ntosylation (TsCl, DMAP), and O-TIPS deprotection (pTsOH) was performed on gram-scale with only one chromatographic workup at the end to give alkenyl triflate 6 in an overall yield of 85% (Scheme 1). This swap of protecting groups became necessary as the Suzuki−Miyaura cross-coupling did not proceed in the presence of the bulky N-TIPS protecting group. On the other hand, the N-tosyl protected derivative of propargyl acetate 4 underwent Au(I)-catalyzed cyclization very slowly affording the cyclopenta[f ]indoline in moderate yield and the intermediate allene (see the Supporting Information (SI)). The desilylation step required acidic conditions because fluoride sources led to decomposition. Suzuki−Miyaura crosscoupling of alkenyl triflate 6 with isobutenyl trifluoroborate 7 yielded the desired diene 8 (95%). Exceeding 50 °C had to be avoided because of protodetriflation to the indene. With diene 8 in hand, we investigated the regio- and diastereoselectivity of the envisioned OH-directed hydrogenation (Scheme 2). Preliminary experiments employing [Rh(dppb)(NBD)]BF4 as catalyst gave promising results affording a mixture of products (see the SI) with 64% de (Table 1).16
As described by Pfaltz et al., the more stable BARF-analogue ([Ir(COD)py(PCy3)]BARF) was envisioned to be more susceptible toward the coordination by the OH-group than the original Crabtree catalyst.18 Unfortunately, in our case, this catalyst was too active, leading to an increased amount of fully reduced product 10 and decreased de’s. Thus, we investigated the temperature dependence of the OH-directed hydrogenation reaction. As expected, the reaction of diene 8 with H2 under Ir-catalysis (entries 5−8, Table 1) proceeds much slower at lower temperatures showing no conversion at −45 °C. Full conversion was achieved after 2 days at −20 °C, affording the desired isobutenyl product 9 in 63% yield and 96% de and a decreased amount of undesired isobutyl product 10. At 0 °C the reaction proceeded within 18 h giving an even better product ratio and an isolated yield of isobutenyl product 9 of 63% and 99% de (Scheme 2). Control experiments employing Wilkinson’s catalyst ([Rh(PPh3)3]Cl) and [Ru((R)BINAP)](OAc)2 did not result in product formation. Reduction using Pd/C or Pd(OH)2/C as catalyst gave fully reduced product 10 in quantitative yield and 20% de. NUnprotected indolines suffered from poor yield in the OHdirected hydrogenation, probably due to competing catalyst coordination. When employing D2 instead of H2, we observed that both deuterium atoms were added to the same face of the indene double bond (bisdeuterated product 9-d2, 72%), as indicated by NOESY correlations of 6-H to the vicinal methyl and isobutenyl groups (Scheme 3). The formation of an
Scheme 2. Ir-Catalyzed OH-Directed Hydrogenation of 1,3Diene 8 and IBX Oxidation
Scheme 3. Deuterium Labeling Study
A variety of Rh- and Ir-catalysts were synthesized by ligand exchange reactions (Table 1).17 Rh-catalysts in all cases gave de values of about 65% of the desired product 9 (as judged by 1H NMR data), as part of an inseparable mixture of products. Ircatalysts had a superior performance in all cases studied, reaching up to 99% de. In addition, only the desired product 9 and the fully reduced product 10 were formed that were separable by column chromatography.
intermediate Ir(V) complex such as 13 would be in agreement with DFT calculations and a kinetic study by Brandt and coworkers19 that has been widely accepted.9e,20 Interestingly, we
Table 1. Rh- or Ir-Catalyzed OH-Directed Hydrogenation of Diene 8 entry
catalyst
time [h]
temp [°C]
yieldc [%] 9:10
de (9)c
1 2 3 4 5 6 7 8 9
[Rh(NBD)(dppb)]BF4a
2 2 5 1 18 48 8 24 0.25
rt rt rt rt 0 °C −20 °C rt −10 °C rt
68:5 59:21 23:61 54:46 74:25 66:26 23:75 62:25 0:100
64% 66% 88% 99% 99% 96% 86% 94% 20%
[Rh(COD)(dppb)]BARFa [Ir(COD)(dppb)]BARFb [Ir(COD)py(PCy3)]PF6a [Ir(COD)py(PCy3)]PF6b [Ir(COD)py(PCy3)]PF6b [Ir(COD)py(PCy3)]BARFb [Ir(COD)py(PCy3)]BARFb Pd/C (5%)a
a
10 mol % catalyst used. b5 mol % catalyst used. cDetermined by 1H NMR spectroscopy 5445
DOI: 10.1021/acs.orglett.8b02349 Org. Lett. 2018, 20, 5444−5447
Letter
Organic Letters
On reaction of 19 (for the synthesis, see the SI) with Ph3PMeBr/LHMDS in THF we did observe the expected Wittig olefination forming vinyl product 20 (Scheme 4). The key difference between starting materials 12 and 19 is the presence of an α-hydrogen in ester 19. We assume that in the case of 19 reprotonation of the lithium alkoxide takes place that allows for the formation of an oxaphosphetane leading to 20. To obtain raputindole A (1), Takai olefination of aldehyde 11 proved to be successful (Scheme 5). At room temperature,
found a 1:1 ratio of 11-epimers in the doubly reduced side product 10-d4, which could be explained by a rather free rotation around the C7−C11 bond. In addition, only 83% deuteration was found at C12, whereas complementary 17% deuteration occurred at the methyl groups of the isobutyl side chain. Apparently, 1,2-hydrogen migration took place to a minor extent.21 For installing the second indole moiety of 1, alcohol 9 was oxidized to aldehyde 11 (IBX, 90%, Scheme 2). We also prepared the saturated analogue 12 by oxidation of 10 (IBX, 89%). Unexpectedly, HWE reaction of aldehyde 12 with indol6-yl methylphosphonate 14 (for the synthesis, see the SI)22 led to formal elimination of formaldehyde to give indene 15 in 35% yield as the sole product after dehydration in CDCl3 (Scheme 4).
Scheme 5. Final Steps toward Raputindole A (1)
Scheme 4. Unexpected Formal Elimination of Formaldehyde on Attempted HWE and Wittig Reactions of Aldehyde 12
elimination product 22 was still formed as minor component of a mixture with the desired (E)-iodoalkene 21 (21:22 = 5:2). Employing 10 equiv of CrCl2 and stirring at 0 °C suppressed the formation of the elimination product 22 (
